1-51236779-C-T

Variant names:

• chr1-51236779-C-T
• rs1317935660
• NM_014372.5:c.23C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_014372.5(RNF11):​c.23C>T​(p.Pro8Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,613,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: RNF11 NM_014372.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.86

Genes affected

RNF11 (HGNC:10056): (ring finger protein 11) The protein encoded by this gene contains a RING-H2 finger motif, which is known to be important for protein-protein interactions. The expression of this gene has been shown to be induced by mutant RET proteins (MEN2A/MEN2B). The germline mutations in RET gene are known to be responsible for the development of multiple endocrine neoplasia (MEN). [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16610244).
• BS2: High AC in GnomAdExome4 at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF11	NM_014372.5	c.23C>T	p.Pro8Leu	missense_variant	Exon 1 of 3	ENST00000242719.4	NP_055187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF11	ENST00000242719.4	c.23C>T	p.Pro8Leu	missense_variant	Exon 1 of 3	1	NM_014372.5	ENSP00000242719.3
RNF11	ENST00000494873.1	n.441C>T		non_coding_transcript_exon_variant	Exon 1 of 2	3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152098 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000121 AC: 3 AN: 248328 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000270

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461342 Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16 AN XY: 726976

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33462

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44672

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26122

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39652

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86206

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53416

Gnomad4 NFE exome AF: 0.0000261 AC: 29 AN: 1111750

Gnomad4 Remaining exome AF: 0.0000166 AC: 1 AN: 60364

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152098 Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1 AN XY: 74278

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000294 AC: 0.0000294048 AN: 0.0000294048

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 10, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.23C>T (p.P8L) alteration is located in exon 1 (coding exon 1) of the RNF11 gene. This alteration results from a C to T substitution at nucleotide position 23, causing the proline (P) at amino acid position 8 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	23
DANN	Benign	0.97
DEOGEN2	Benign	0.089	T
Eigen	Benign	-0.053
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.15
Sift	Benign	0.34	T
Sift4G	Benign	0.31	T
Polyphen		0.0010	B
Vest4		0.41
MVP		0.28
MPC		0.97
ClinPred		0.41	T
GERP RS		4.6
Varity_R		0.39
gMVP		0.46
Mutation Taster		=55/45	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1317935660; hg19: chr1-51702451;